Transdermal patches are used for the application of drugs through the skin. After sticking a transdermal patch onto the skin, a drug suitable for this application continuously enters the systemic bloodstream in a direct way, i.e. by bypassing the gastrointestinal tract and the first liver passage, whereby e.g. gastric intolerance and/or the early hepatic ‘first-pass’ effect (decomposition in the liver) of certain substances after oral administration is avoided. Examples of this include nicotine patches, hormone patches and pain-relieving patches, as well as transdermal patches for treatment of Parkinson's disease, or for treatment of ‘restless legs’. Therapeutic patches of this type can contain the dopaminergic active substance rotigotine. Inter alia, it is suitable for treating Parkinson's disease, and for therapy on restless legs, and corresponding transdermal patches are already used in some countries. Medical uses of rotigotine or pharmaceutical forms containing rotigotine are described, for example, in WO 2005/92331, WO 2005/009424, WO 2007/147556, WO 03/92677, as well as WO 2005/63237.
A preferred embodiment of a transdermal patch known in the prior art consists of an active substance layer, a carrier layer and a release liner film. Patches designed in this way are generally punched out of an large-area laminate. After this punching, the active layer is open on the peripheral separating edges, i.e. is not covered by films.
A possible manufacturing of rotigotine patches, which correspond to the above-mentioned embodiment, is described in WO 02/089778 and WO 04/012730, for example. In the process, the active substance rotigotine is contained in a non-crystalline form in a layer containing silicone adhesive. Before introducing rotigotine in the adhesive layer, rotigotine is dissolved in a solvent, and the solvent containing adhesive, loaded with the active substance, is applied in a subsequently continuous coating process on a release liner film, a polyester film, also denoted as a ‘release liner’ or ‘protective film’, and the solvent is removed by heating in a drying channel. After the drying process, a carrier layer, which is impermeable for the active substance, is laminated onto the remaining open interface of the rotigotine containing adhesive layer. The laminate manufactured in this way is subsequently divided in individual patches by mechanical separation.
The separating edges between the individual patches are conventionally created by mechanical separation, for example, by cutting or punching through. Additionally, the release liner film can also be provided with an S-shaped cut, the so called ‘S-cut’. This cut facilitates a removal of the release liner film from the patch, in order to stick the patch with its rotigotine containing adhesive layer onto the skin of a patient. On one hand, the S-cut can be realised as a continuous cut along the whole patch, or as a ‘predetermined breaking point’ in the form of specific weakening of the release liner film along an S-cut line. In addition to the above-described form, this ‘cut’ or ‘predetermined breaking point’ can comprise other forms, such as the form of a straight or zigzag line. A possible manufacturing process for a transdermal patch is for example described in detail in WO 04/012730, as example 1, beginning on page 14.
However, when the patch created in this way is stored at room temperature, there is a risk that in the active substance layer rotigotine crystal formation occurs in the region of the separating edges, and spread, originating from the edges of the patch or the S-cut of the release liner film in the direction of the inside of the active substance layer, thus away from the corresponding edge, but also along the edge. FIG. 1 shows a separating edge 18 of a patch containing rotigotine, from which crystals 20 are spreading into the active substance layer 14. Rotigotine crystals can form different polymorphs, which can occur alone as well as in a mixture (e.g. form I and form II). In general, the resulting crystals form a thermodynamically stable polymorph II (‘form II’) of rotigotine. The formation of a crystalline polymorph of this type is undesired in a patch formulation; efforts are therefore made to avoid crystallisation. For this purpose, in some cases up to now, a continuous cooling of the patch is implemented, in order to inhibit the growth of the crystals. However, this requires high logistic effort and expenditure in order to maintain the cold chain from the manufacturing of the patch until its application on patients, and is very difficult to implement in some countries. In addition, the assistance of each patient is required, and therefore the application is more difficult for the patient.
Such a crystallisation of the active substance in the region of the matrix edges, which are open in relation to the environment, also represents a problem for patches with different active substances. This particularly applies to silicone-based patches, whose matrix has a higher permeability for water vapour and oxygen, and for lipophilic, particularly poorly water soluble active substances.